Nick E. Goeders

Non-contingent electric footshock facilitates the acquisition of intravenous cocaine self-administration in rats

The experiments described below were designed to investigate whether contingent versus non-contingent electric footshock would affect the acquisition of intravenous cocaine self-administration in rats. During the first component of a multiple schedule, triads of rats were trained to respond under a discrete-trial, fixed-ratio 10 schedule of food reinforcement. Random footshock presentation (0.6 mA) for the first and second rats from each triad was yoked to food lever responding by the rats in the first group only, while the third group of rats was never shocked. When stable baselines of food-reinforced responding were obtained, all three rats from each triad were allowed to self-administer increasing doses of cocaine (0.031–0.5 mg/kg per infusion) during the second component. Rats from the second group, receiving noncontingent footshock presentation, self-administered cocaine (0.125 mg/kg per infusion) at higher rates and at one-half the dose which maintained responding in rats from the other two treatment groups. Plasma corticosterone, measured before the acquisition of cocaine self-administration, was highly correlated with drug intake at this concentration for all three groups of rats. These data demonstrate that non-contingent experimental stress facilitates the acquisition of intravenous cocaine self-administration in rats.

Self-administration of methionine enkephalin into the nucleus accumbens

Microinfusions of the endogenous opiate neurohumor, methionine enkephalin, into the nucleus accumbens initiated a reinforcing stimulus in a dose-related manner. The reinforcing nature of this intracranial self-administration was evaluated with intermittent schedules of reinforcement and a two-lever discrimination procedure. Opiate receptors are likely responsible for the initiation of this reinforcing stimulus since naloxone effectively blocked self-administration. These data suggest the mediation of opiate reinforcement through interactions with opiate receptors in brain regions outside the ventral tegmental area, questioning the current dopamine hypothesis for the initiation of these reinforcement processes.

The HPA axis and cocaine reinforcement

Scientists have been aware of the existence of a complex relationship between stress and the subsequent activation of the hypothalamic-pituitary-adrenal (HPA) axis and the endocrine and neurobehavioral effects of cocaine for many years now. Our research program has focused on the involvement of HPA axis activation in cocaine reinforcement using the intravenous self-administration model. Behaviorally, there are at least three general phases in the etiology of drug self-administration to consider: acquisition, maintenance and reinstatement. We have investigated the role for the HPA axis during each of these three phases. Corticosterone is necessary during acquisition; self-administration does not occur unless this stress-related hormone is increased above a threshold critical for reward. Sensitivity to low doses of cocaine falling on the ascending limb of the acquisition dose-response curve can be augmented by increasing circulating levels of corticosterone, but similar treatments do not affect responding maintained by higher doses. In a similar vein, ongoing, low-dose cocaine self-administration is decreased by drugs affecting the synthesis and/or secretion of corticosterone. When higher doses falling on the descending limb of the cocaine dose-response curve are self-administered, plasma corticosterone can still reach this hypothetical reward threshold even when synthesis is inhibited, and drug intake is not affected. On the other hand, the self-administration of doses falling on both the ascending and descending limbs of the cocaine dose-response curve can each be attenuated by drugs that block central corticotropin-releasing hormone (CRH) receptors. Finally, corticosterone and CRH are also critical for the stress- and cue-induced reinstatement of extinguished cocaine-seeking behavior, demonstrating an involvement of the HPA axis in the relapse to cocaine use as well. Continued investigations into how stress and the subsequent activation of the HPA axis affect cocaine self-administration will likely result in the identification of more effective and efficient treatment for cocaine addiction.

A neuroendocrine role in cocaine reinforcement

Cocaine stimulates the secretion of corticosterone and ACTH, probably through a CRF-related mechanism, indicating that the drug activates the HPA axis. Indeed, cocaine has been reported to produce anxiety and to precipitate episodes of panic attack during chronic use and withdrawal in humans and to induce anxiogenic behavior in animals. Cocaine also alters benzodiazepine receptor binding in discrete regions of the rat brain. Some of these changes in binding are obviously related to the convulsions and seizures which are often observed in an acute cocaine overdose. However, data from behavioral studies have suggested that some of these effects may be related directly to cocaine reinforcement since receptor changes also were observed when binding in the brains of rats that self-administered cocaine was compared with that from animals that had received identical yoked, but non-contingent infusions of the drug. In this regard, pretreatment with the benzodiazepine receptor agonists chlordiazepoxide and alprazolam decreased cocaine self-administration without decreasing food-reinforced responding, suggesting that these effects were specific for cocaine. Since this attenuation of self-administration was reversed by increasing the unit dose of cocaine, it is likely that these drugs were decreasing cocaine reinforcement. In contrast, exposure to stress increases vulnerability to self-administer psychostimulants. In these experiments, low-dose cocaine self-administration was related directly to stress-induced increases in plasma corticosterone, such that plasma corticosterone was always greater than 150 ng/ml for rats which subsequently self-administered cocaine at doses of 0.125 mg/kg/infusion or lower, suggesting a threshold for the hormone in cocaine reinforcement. In other experiments, bilateral adrenalectomy completely abolished the acquisition of intravenous cocaine self-administration in naive rats, while metyrapone decreased ongoing self-administration. In addition, ketoconazole pretreatment resulted in patterns of self-administration that were virtually indistinguishable from that observed during saline extinction, suggesting that plasma corticosterone is not only important, but may even be necessary for cocaine reinforcement. The mechanisms through which adrenocorticosteroids alter cocaine reinforcement remain to be determined, but there is increasing evidence that the mesocorticolimbic dopaminergic system is involved. In particular, the medial prefrontal cortex appears to be at least one brain region where dopamine and adrenocorticosteroids may interact to affect cocaine reinforcement.

Reinforcing properties of cocaine in the medial prefrontal cortex: Primary action on presynaptic dopaminergic terminals

The presynaptic mechanisms involved in the initiation of cocaine reinforcement were investigated using neurotoxin lesions. Rats were trained to intracranially self-administer cocaine (50 to 90 pmol) into the medial prefrontal cortex and after dose-effect analyses were completed, each rat received a unilateral 6-hydroxydopamine lesion (4 micrograms in 0.2 microliter) at the self-administration site. The lesion selectively decreased dopamine content in the medial prefrontal cortex (-45%) and decreased cocaine-maintained responding to vehicle levels. Lever-pressing could be reinstated by substituting dopamine (300 pmol) but not serotonin for cocaine. Dopamine self-administration was attenuated by including equimolar concentrations of the D2 dopaminergic antagonist sulpiride in the injectate. These results suggest that the initiation of reinforcing neuronal activity in the medial prefrontal cortex appears to result in part through the direct interaction of cocaine with presynaptic reuptake sites associated with dopaminergic nerve endings. The resulting increased synaptic concentration of the neurotransmitter may then interact with postsynaptic D2 binding sites to activate neuronal systems involved in the mediation of this reinforcement.

Role of Corticosterone in Intravenous Cocaine Self-Administration in Rats

The role of corticosterone in cocaine reinforcement was investigated in rats exposed to either response-contingent electric footshock, noncontingent shock or no shock prior to the initiation of testing for intravenous cocaine self-administration. Although rats from the two shock groups were consistently more sensitive to cocaine, plasma corticosterone was always significantly higher in all rats that subsequently self-administered low doses of cocaine compared to the rats that did not, regardless of the treatment condition. In fact, plasma corticosterone was always greater than approximately 150 ng/ml for rats that self-administered low doses of cocaine, suggesting that this stress hormone must be increased above a critical threshold for stable low-dose cocaine self-administration to subsequently occur. Plasma corticosterone was also measured following exposure to cocaine and was significantly elevated in rats from all three treatment groups during cocaine self-administration, provided that doses of cocaine that would maintain responding were tested. When the dose would not maintain self-administration, plasma corticosterone was markedly lower, suggesting that at higher concentrations, the cocaine injections alone were sufficient to increase plasma corticosterone above a critical threshold, even for rats which had low precocaine levels of the hormone. These data suggest a significant role for corticosterone in both the acquisition and maintenance of cocaine reinforcement in rats.

Anxiogenic effects of acute and chronic cocaine administration : neurochemical and behavioral studies

The effects of cocaine on defensive withdrawal behavior in rats and elevated plus-maze behavior in mice were investigated. Cocaine (20 mg/kg IP) injected daily for 7 or 14 days induced defensive withdrawal; that is, the latency to emerge from a small chamber in an open field and the mean time in the chamber were both significantly increased. Acute cocaine administration also induced defensive withdrawal, and this effect was prevented by prior treatment with chlordiazepoxide (5 mg/kg IP). Both acute and chronic cocaine treatments significantly increased plasma concentrations of corticosterone and reduced the ratios of 3,4-dihydroxyphenylacetic acid to dopamine and 5-hydroxyindoleacetic acid to serotonin in several brain regions. Further evidence for an acute anxiogenic effect of cocaine was obtained from mice studied in the elevated plus-maze. Acute cocaine administration decreased both the number of entries into and the time spent in the open arms of the maze. These results taken together strongly support an anxiogenic action of acute and chronic cocaine administration.

Neuropharmacological assessment of cocaine self-administration into the medial prefrontal cortex

Neuronal systems involved in the initiation of reinforcement following the response-contingent delivery of cocaine into the medial prefrontal cortex were investigated. Dose-effect analyses demonstrated that different concentrations of cocaine result in distinguishable patterns of self-administration which could be empirically determined by measuring the relative frequency distribution of the interinfusion intervals. The substitution of equimolar d-amphetamine or lidocaine resulted in rates and patterns of responding similar to vehicle or a low dose of cocaine, suggesting that reinforcement occurs from actions on specific receptors rather than through a local anesthetic neuronal blockade or through properties of a general psychomotor stimulant. The co-infusion of equimolar concentrations of sulpiride attenuated intake and produced patterns of responding similar to those seen after decreasing the cocaine dose consistent with an excitatory role for D2 dopaminergic receptors in these processes. Sulpiride and cocaine may act at separate sites since the decreased intake was not reversed by increasing the concentration of cocaine. D1 dopaminergic, muscarinic-cholinergic and beta-noradrenergic receptor antagonists either did not modulate drug-intake or had minimal effects. Cocaine reinforcement may result in part from an activation of D2 receptors initiating neuronal activity in pathways or circuits mediating reinforcement processes.

Ketoconazole blocks the stress-induced reinstatement of cocaine-seeking behavior in rats: relationship to the discriminative stimulus effects of cocaine.

Abstract  Rationale: Ketoconazole (Keto) is an antifungal agent that also inhibits the synthesis of adrenocorticosteroids and has been reported to act as a glucocorticoid receptor antagonist. Objective: The present experiments investigated the effects of Keto on the stressor-induced reinstatement of extinguished cocaine-seeking behavior and on the generalization of a stressor-induced discriminative stimulus to cocaine in rats. Methods: In the first experiment, male Wistar rats were trained to self-administer cocaine (0.5 mg/kg per infusion, IV) under a fixed-ratio 4 schedule of reinforcement with a 90-s limited hold. Following ten consecutive extinction sessions, the effects of Keto (25 or 50 mg/kg, IP) or vehicle on the ability of EFS (electric footshock; 15 min) to reinstate extinguished cocaine-lever responding were investigated. In the second experiment, rats were trained to discriminate cocaine (10 mg/kg, IP) from saline using a two-lever, food-reinforced drug discrimination design. The effects of Keto (50 mg/kg, IP) or vehicle on the EFS-induced generalization to cocaine were determined. Results: EFS reinstated extinguished cocaine- but not food-reinforced responding. Keto (25 and 50 mg/kg, IP) blocked the EFS-induced reinstatement of cocaine-seeking behavior and significantly attenuated the plasma corticosterone response to EFS. These same doses of Keto failed to affect responding in rats trained to self-administer food pellets under an FR4 schedule of reinforcement. EFS also produced significant cocaine-appropriate responding in rats trained to discriminate the drug from saline. However, Keto (50 mg/kg) failed to block the EFS-induced generalization to cocaine. Conclusions: Overall, these data suggest that corticosterone contributes to the stressor-induced reinstatement of extinguished cocaine-seeking behavior.

Chlordiazepoxide alters intravenous cocaine self-administration in rats ☆

This investigation was designed to examine the effects of benzodiazepines on intravenous cocaine self-administration in rats. Pretreatment with low doses of the benzodiazepine receptor agonist, chlordiazepoxide (0.3 to 1.0 mg/kg, IP), resulted in small but nonsignificant increases in drug intake with 0.5 mg/kg cocaine, while higher doses (10 mg/kg, IP) significantly decreased drug intake in all rats tested. The effects of chlordiazepoxide on self-administration were attenuated when the concentration of cocaine was increased to 1.0 mg/kg, suggesting that chlordiazepoxide was opposing rather than augmenting the pharmacological actions of cocaine. Pretreatment with the benzodiazepine receptor antagonist, Ro 15-1788 (1.0 to 10 mg/kg, IP), had no effect on self-administration, suggesting that the reinforcing properties of cocaine do not result from direct interactions with benzodiazepine receptors. The result of this investigation demonstrate that chlordiazepoxide alters intravenous cocaine self-administration in rats. Although additional research will be necessary to confirm these data, the results of this investigation suggest that chlordiazepoxide may decrease the reinforcing efficacy of cocaine through indirect actions on dopaminergic neuronal activity potentially mediated through GABAergic mechanisms via benzodiazepine receptor activation.